Diabetes mellitus afflicts 20.8 million people, or 7% of the population, in the United States. Fifteen percent, or 2.4 million people, will develop diabetic foot ulcers in their life time. Diabetic foot ulceration and infections are a major cause of hospitalization of diabetic patients. The direct and indirect costs of ulcer management and treatment exceed 10 billion dollars per year. In spite of this, approximately 1000 amputations are still performed on people with diabetes each week in the USA due to the lack of effective therapy for diabetic foot ulcers. Attempts to treat diabetic foot ulcers with growth factors have resulted in little success. Increasing evidence indicates that TGF-[unreadable] is involved in the early and late phases of peripheral neuropathy and microvascular disease, both of which contribute to the development of diabetic foot ulcers. In diabetic patients, the plasma level of TGF-[unreadable] is increased; TGF-[unreadable] expression is also increased in diabetic wounds. TGF-[unreadable] is a potent chemoattractant for inflammatory cells and inhibitor of endothelial and epithelial cell growth. It has been implicated in prolonged inflammation, defective angiogenesis and retarded wound re-epithelialization, as seen in diabetic foot ulcers. TGF-[unreadable] appears to be an ideal therapeutic target for treating diabetic foot ulcers. However, no effective TGF-[unreadable] antagonists have been developed. Recently, we developed TGF-[unreadable] peptide antagonists (termed TGF-[unreadable] peptantagonists) which are the only known TGF-[unreadable] receptor antagonists and have been shown to accelerate normal wound healing in several animal burn/excision wound models. The efficacy of TGF-[unreadable] peptantagonists in accelerating wound healing is limited by its poor solubility in aqueous solutions at neutral pH. The proposed research aims at developing novel TGF-[unreadable] antagonists with excellent solubility, potent activity and high wound-penetration activity, based on the current chemical forms of TGF-[unreadable] peptantagonists. The new forms of TGF-[unreadable] peptantagonists developed in these studies should be excellent candidate drugs for treating diabetic foot ulcers. PUBLIC HEALTH RELEVANCE the goal of this project is to develop therapeutic agents for diabetic foot ulcers which currently lack effective treatments. The novel antagonists developed in this project should be ideal drug candidates for treating diabetic foot ulcers in humans. [unreadable] [unreadable] [unreadable]